My career goal is to have an independent research laboratory exploring the direct neuronal signaling pathways in the paraventricular nucleus (PVN) that influence hypertension. The PVN is an integrative region of the hypothalamus involved in the regulation of metabolic processes, stress responses, cardiovascular function/blood pressure regulation and the autonomic nervous system. The overall hypothesis is that sodium-dependent hypertension is associated with increased excitatory neurotransmission and hypertension that is the result of changes within the PVN. In part due to altered paracrine signaling, specifically nitric oxide (NO) and superoxide (O2-) interactions, influencing neurotransmitters. In addition, an upregulation of intracellular signaling families, phosphatidylinositol 3-kinase (PI3-kinase) and mitogen activated protein kinase (MARK), further amplifies excitatory neurotransmission resulting in hypertension. The goal is to use an integrative approach, using biochemical, gene transfer and physiological studies, to examine how both paracrine and intracellular signaling changes in the PVN to increase excitatory sympathoadrenal function and elevate blood pressure. To achieve this goal 4 hypotheses will be addressed (2 during the mentored period and 2 during the independent portion of the grant): Hypothesis #1: NAD(P)H oxidase is present in the PVN and its activity is increased by Ang II and glutamate, thus elevating O2- levels in renal wrap hypertension. Hypothesis #2: In renal wrap hypertension, there is elevated O2- which combines with NO, reducing bioavailable NO and ultimately increasing sympathoadrenal function and blood pressure. Hypothesis #3: Ang II via the AT1 receptor and Glutamate via the NMDA receptor utilize common signaling pathways involving an upregulated PI3-kinase signaling cascade, increasing O2-, in turn, elevating excitatory neurotransmission in hypertension. Hypothesis #4: Enhanced O2- levels act as signaling molecules that lead to the activation of the MAPK signaling cascade in the PVN, ultimately elevating excitatory neurotransmission in hypertension. Identifying the changes in paracrine and intracellular signaling pathways is significantly important for understanding the impact signaling pathways have on neurotransmitter activity and hypertension. In addition, due to the integrative nature of the PVN, these data will also provide a glimpse at the role of signaling in other physiological conditions, such as obesity.